Farnesyltransferase regulates neutrophil recruitment and tissue damage in acute pancreatitis

Mohammed Merza, Darbaz Awla, Rundk Hwaiz, Milladur Rahman, Stefan Appelros, Aree Abdulla, Sara Regner, Henrik Thorlacius
Pancreas 2014, 43 (3): 427-35

OBJECTIVES: The signaling mechanisms controlling organ damage in the pancreas in severe acute pancreatitis (AP) remain elusive. Herein, we examined the role of farnesyltransferase signaling in AP.

METHODS: Pancreatitis was provoked by the infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a farnesyltransferase inhibitor FTI-277 (25 mg/kg) before pancreatitis induction.

RESULTS: FTI-277 decreased the blood amylase levels, pancreatic neutrophil infiltration, hemorrhage, and edema formation in the pancreas in mice challenged with taurocholate. Farnesyltransferase inhibition reduced the myeloperoxidase levels in the pancreas and lungs in response to taurocholate infusion. However, FTI-277 had no effect on the taurocholate-provoked formation of macrophage inflammatory protein-2 in the pancreas. Interestingly, farnesyltransferase inhibition abolished the neutrophil expression of macrophage-1 antigen in mice with pancreatitis. In addition, FTI-277 decreased the taurocholate-induced activation of the rat sarcoma protein in the pancreas. An important role of farnesyltransferase was confirmed in L-arginine-induced pancreatitis.

CONCLUSIONS: These results demonstrate that farnesyltransferase signaling plays a significant role in AP by regulating neutrophil infiltration and tissue injury via the neutrophil expression of macrophage-1 antigen. Thus, our findings not only elucidate novel signaling mechanisms in pancreatitis but also suggest that farnesyltransferase might constitute a target in the management of severe AP.


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